Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

Research output: Contribution to journalArticle

Authors

  • Pia Rantakari
  • Joona Valtonen
  • Marika Karikoski
  • Heidi Gerke
  • Harriet Dawes
  • Juha Laurila
  • Steffan Ohlmeier
  • Kati Elima
  • Sirpa Jalkanen
  • Marko Salmi

External organisations

  • Department of Medical Microbiology & Immunology, University of Turku, Finland

Abstract

Macrophages are key regulators of fibrosis development and resolution. Elucidating the mechanisms by which they mediate this process is crucial for establishing their therapeutic potential. Here, we use experimental models of liver fibrosis to show that deficiency of the scavenger receptor, stabilin-1, exacerbates fibrosis and delays resolution during the recovery phase. We detected a subset of stabilin-1+ macrophages which were induced at sites of cellular injury close to the hepatic scar in mouse models of liver fibrosis and in human liver disease. Stabilin-1 deficiency abrogated malondialdehyde-LDL (MDA-LDL) uptake by hepatic macrophages and was associated with excess collagen III deposition.

Mechanistically, the lack of stabilin-1 led to elevated intrahepatic levels of the pro-fibrogenic chemokine CCL3 and an increase in GFAP+ fibrogenic cells. Stabilin-1-/- macrophages demonstrated a pro-inflammatory phenotype during liver injury and the normal induction of Ly6Clo monocytes during resolution was absent in stabilin-1 knockouts leading to persistence of fibrosis. Human stabilin-1+ monocytes efficiently internalised MDA-LDL and this suppressed their ability to secrete CCL3 suggesting that loss of stabilin-1 removes a brake to CCL3 secretion.

In support of this, studies with cell lineage specific knockouts revealed that stabilin-1 expression in myeloid cells is required for the induction of this novel subset of macrophages and that increased fibrosis occurs in their absence. This study demonstrates a new regulatory pathway in fibrogenesis in which a macrophage scavenger receptor protects against organ fibrosis by removing fibrogenic products of lipid peroxidation. Thus stabilin-1+ macrophages shape the tissue microenvironment during liver injury and healing.

Details

Original languageEnglish
Pages (from-to)9298–9303
JournalNational Academy of Sciences. Proceedings
Volume113
Issue number33
Early online date29 Jul 2016
Publication statusPublished - 16 Aug 2016

Keywords

  • Stabilin-1, chronic liver injury, macrophages, fibrosis development